NEW YORK – Transposable element (TE) promoters that get reactivated in cancer cells can lead to chimeric transcripts involving parts of protein-coding genes, resulting in cancer-specific cell surface antigens, a new study has found. The findings point to potential new treatment strategies, including immunotherapy and a pan-cancer vaccine.
TEs, also referred to as jumping genes, make up nearly 50 percent of the human genome but generally no longer actively transpose. Previous studies have shown that epigenetic dysregulation of TEs in cancer cells can result in the reactivation of cryptic promoters — a process known as promoter exaptation — that can upregulate many oncogenes.
Transcripts that start at TEs can also splice into close-by protein-coding genes, leading to chimeric transcripts that are translated into unique tumor-specific peptides and can be presented on the cell surface of cancer cells.
According to the study authors, who embarked on a systematic search of these TE-chimeric transcripts, such epitopes could become potential targets for immunotherapy and other cancer drugs.
"Our study provides a completely different way of discovering new antigens," said corresponding author Ting Wang, a professor of medicine at Washington University School of Medicine in St. Louis. Since the project found novel antigens across cancer types, this could also pave the way for developing a pan-cancer vaccine, he added.
For their study, published in Nature Genetics on Monday, Wang and colleagues performed a comprehensive screen of TE-chimeric transcripts in 11,086 samples across 33 TCGA (The Cancer Genome Atlas) tumor types, 11,686 samples from 30 Genotype-Tissue Expression (GTEx) adult tissues, and 675 cancer cell lines.
They found 26,816 TE-chimeric transcripts across the samples and used stringent filtering criteria to narrow the list down to 2,297 unique transcripts across all cancer types.
"We looked at what kind of proteins these transcripts would make," said lead author Nakul Shah, a medical student in Wang's laboratory. "We found that thousands of these transcripts could make unique sequences that are only present in cancer cells, not normal cells," he added.
Subsequent experiments using mass spectrometry validated the presence of these proteins on HLA molecules on cancer cells. The question of whether the human immune system recognizes these antigens, however, remained unanswered and was one of the limitations of this study, Shah said.
The analysis also found that tumors with TP53 mutations were more likely to have TE-chimeric transcripts. This finding suggested that TP53 mutations could serve as a promising biomarker for prioritizing TE-focused therapeutic interventions.
Meanwhile, the researchers also found that some of the TE-chimeric transcripts became parts of transmembrane proteins in cancer cells. "This opens potential therapeutic avenues of using antibody-based or CAR T-cell therapies without the restrictive need for TE-chimeric peptides to be presented on HLA molecules," the authors noted.
Wang also pointed out that the study could prompt yet another way of thinking about cancer treatment, by epigenetic manipulation. "After all, it is the epigenetic deregulation of TEs which leads to all these downstream effects. It gives us hope that we can epigenetically control the production of these (chimeric) antigens," he said.